! PROJECT SUMMARY: This application's broad, long-term objective is to improve the health of millions of Americans with or at risk for obesity- associated non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the United States. After successfully validating MR imaging biomarkers for hepatic steatosis, the earliest histologic feature of NAFLD, in the first cycle of this grant, this competitive renewal focuses on hepatic fibrosis and inflammation, features of non-alcoholic steatohepatitis (NASH), the aggressive subtype of NAFLD that can progress to cirrhosis, liver cancer, and liver-related death. MR elastography (MRE), a noninvasive method to quantify tissue stiffness, is the leading imaging-based technique for assessing liver fibrosis in NAFLD, but the true diagnostic performance of MRE for detecting fibrosis and NASH cross-sectionally, and for monitoring their change longitudinally, is incompletely understood. By optimizing and rigorously evaluating MRE for these purposes, we will address major knowledge and technical gaps that have obscured the appropriate utilization of this technology in clinical care and research. Aim 1: Optimize MRE wavefield generation in severe obesity, applicable to both conventional 2D- and advanced 3D-MRE. Aim 2: Characterize the precision profile of conventional 2D- and advanced 3D-MRE in severe obesity (same-day repeatability, field-strength reproducibility, reader reproducibility, between-day reproducibility). Aim 3: Determine the accuracy of conventional 2D- and advanced 3D-MRE in severe obesity to a) diagnose fibrosis and NASH cross-sectionally and b) monitor change in fibrosis and resolution of NASH longitudinally. Significance: By determining the true diagnostic performance of conventional 2D- and advanced 3D-MRE for detecting and monitoring fibrosis and NASH in bariatric patients, the proposed research will inform the appropriate utilization of MRE for clinical care, clinical trials, and other research in obesity-associated NAFLD. Additionally, if the research confirms the promise of advanced 3D-MRE to detect early-stage NASH, this will represent a game-changing new technical capability. Innovation: This application brings innovation in three thematic areas: (1) Study design: prospective cross-sectional and longitudinal study in bariatric patients, a technically challenging population with balanced disease severity distribution ideal for addressing the scientific aims. (2) Wavefield generation: testing of new flexible drivers designed to generate high-quality wavefields. (3) MRE analysis: rigorous testing of advanced 3D-MRE reconstruction and analysis methods that in preliminary animal and human studies show promise for diagnosing early-stage NASH. Research design & methods: Phase 1 of this 2-site study will optimize MRE wavefield generation in severe obesity by identifying the driver type and position that maximize MRE precision. Using that optimal driver type/position, Phase 2 will enroll 100 severely obese adults (50/site) undergoing weight-loss surgery in a prospective longitudinal study with 2D- and 3D-MRE at multiple time points. Reference standards for the presence of fibrosis and NASH, and their change, will include expert consensus scoring and quantitative image analysis of paired contemporaneous biopsies obtained at surgery and at 6 months. Complementary anthropometric, laboratory, and MRI measures will be acquired to identify factors that affect MRE performance and develop hypotheses for future studies. !